The cost of the rapid scale-up in prescribing highly active antiretroviral therapy (HAART) for HIV has been significant in terms of side-effects related to brain aging (Heaton et al., 2011; Green et al., 2005; Giunta et al., 2011). There is a need to phase in less toxic HAART regimens. We designed an experiment to understand the interactions between brain aging, HIV-1 Tat protein, and the known cognitive side-effects imparted by chronic HAART (Ciccarelli et al., 2011). We preliminarily found efavirenz (EFV)/lamivudine (3TC)/zidovudine (AZT), a commonly used HAART regimen, promoted ROS production, BACE1 expression, and A? generation both in vitro and in vivo in Tg2576 amyloid depositing mice. This HAART regimen significantly inhibited microglial phagocytosis of A?1-42 peptide as well. Regarding these outcomes, EFV was most potent while AZT was least potent. Additionally we have found that HIV-1 Tat protein inhibits microglial phagocytosis of A? peptide (Giunta et al., 2008a) and that it contributes to aging pathology in HIV-1 Tat/PSAPP transgenic mice (Giunta et al., 2009). Here we plan to characterize neurocognition, and advanced brain aging pathology in HIV-1 Tat /PSAPP mice chronically treated with HAART. EFV/3TC/AZT should lead to advanced neurocognitive deficits in these mice by 12 months of age that should be synergistically enhanced by brain HIV-1 Tat expression which that can be correlated with elevations in A?1-42/?-CTF, compared to control, EFV, AZT, or 3TC treated mice. This will allow us to isolate which antiretroviral(s) in this commonly used regimen are most neurotoxic during chronic administration. We expect that other indicators of this will outcome will include elevations of AD-like hyperphosphorylated tau, pro-inflammatory cytokines, and dysregulation of microglial A? phagocytosis, and brain mitochondrial function. This study is expected to describe the long-term consequences of chronic Tat expression with use of a common HAART regimen in terms of advanced brain aging-like neuropathology and cognitive deficits. It should lay the foundation for effective strategies to prevent these interactions between Tat and HAART in the future in the context of a known HAART-mediated pathophysiological mechanism.